Erich C. Strauss

Effector Mechanisms of the Autoimmune Syndrome in the Murine Model of Autoimmune Polyglandular Syndrome Type 1

Mutations in the Aire gene result in a clinical phenomenon known as Autoimmune Polyglandular Syndrome (APS) Type I, which classically manifests as a triad of adrenal insufficiency, hypoparathyroidism, and chronic mucocutaneous infections. In addition to this triad, a number of other autoimmune diseases have been observed in APS1 patients including Sjögren’s syndrome, vitiligo, alopecia, uveitis, and others. Aire-deficient mice, the animal model for APS1, have highlighted the role of the thymus in the disease process and demonstrated a failure in central tolerance in aire-deficient mice. However, autoantibodies have been observed against multiple organs in both mice and humans, making it unclear what the specific role of B and T cells are in the pathogenesis of disease. Using the aire-deficient mouse as a preclinical model for APS1, we have investigated the relative contribution of specific lymphocyte populations, with the goal of identifying the cell populations which may be targeted for rational therapeutic design. In this study, we show that T cells are indispensable to the breakdown of self-tolerance, in contrast to B cells which play a more limited role in autoimmunity. Th1 polarized CD4+ T cells, in particular, are major contributors to the autoimmune response. With this knowledge, we go on to use therapies targeted at T cells to investigate their ability to modulate disease in vivo. Depletion of CD4+ T cells using a neutralizing Ab ameliorated the disease process. Thus, therapies targeted specifically at the CD4+ T cell subset may help control autoimmune disease in patients with APS1.

Small Proline-Rich Protein 1B (SPRR1B) Is a Biomarker for Squamous Metaplasia in Dry Eye Disease

PURPOSE Squamous metaplasia occurs in ocular surface diseases like Sjögrens syndrome (SS). It is a phenotypic change whereby epithelial cells initiate synthesis of squamous cell-specific proteins such as small proline-rich protein 1B (SPRR1B) that result in pathologic keratin formation on the ocular surface. The authors hypothesized that inflammation is a key inducer of pathologic keratinization and that SPRR1B represents an analytical biomarker for the study of the molecular mechanisms. METHODS Real-time quantitative RT-PCR and immunohistochemistry were used to examine SPRR1B mRNA and protein in two different mouse models of dry eye and patients with SS. Adoptive transfer of mature lymphocytes from mice lacking the autoimmune regulator (aire) gene was performed to examine the role of inflammation as an inducer of squamous metaplasia. SPRR1B expression in response to several cytokines was examined in vitro, whereas the expression of cytokines IL1beta and IFNgamma was quantified in ocular tissues of aire-deficient mice and patients with SS. RESULTS SPRR1B was increased across the ocular surface of mice with both desiccating stress and autoimmune-mediated, aqueous-deficient dry eye and in patients with SS. Adoptive transfer of CD4(+) T cells from aire-deficient mice to immunodeficient recipients caused advanced ocular surface keratinization. IL1alpha, IL1beta, IL6, IFNgamma, and TNFalpha induced SPRR1B expression in vitro and the local expression of IL1beta and IFNgamma was elevated in ocular tissues of patients with SS and aire-deficient mice. CONCLUSIONS SPRR1B is a valid biomarker for the study of the molecular mechanisms of squamous metaplasia. There is a definitive link between inflammation and squamous metaplasia in autoimmune-mediated dry eye disease, with IL1beta and IFNgamma likely acting as key participants.

An Autoimmune Response to Odorant Binding Protein 1a Is Associated with Dry Eye in the Aire-Deficient Mouse

Sjögren’s Syndrome (SS) is a human autoimmune disease characterized by immune-mediated destruction of the lacrimal and salivary glands. In this study, we show that the Aire-deficient mouse represents a new tool to investigate autoimmune dacryoadenitis and keratoconjunctivitis sicca, features of SS. Previous work in the Aire-deficient mouse suggested a role for α-fodrin, a ubiquitous Ag, in the disease process. Using an unbiased biochemical approach, however, we have identified a novel lacrimal gland autoantigen, odorant binding protein 1a, targeted by the autoimmune response. This novel autoantigen is expressed in the thymus in an Aire-dependent manner. The results from our study suggest that defects in central tolerance may contribute to SS and provide a new and clinically relevant model to investigate the pathogenic mechanisms in lacrimal gland autoimmunity and associated ocular surface sequelae.

Late varicella-zoster virus dendriform keratitis in patients with histories of herpes zoster ophthalmicus.

PURPOSE To describe the characteristics and course of late varicella-zoster virus (VZV) dendriform keratitis in patients with histories of herpes zoster ophthalmicus (HZO); to describe responses of corneal lesions to antiviral treatment; and to investigate risk factors for recurrence. DESIGN Retrospective case series. METHODS Included were patients known to have 1 or more episodes of dendriform lesions beginning at least 2 weeks after HZO in 2 academic practices. Epithelial lesions were evaluated for the presence of VZV DNA by a polymerase chain reaction assay. Demographic, medical, and ophthalmic data were collected for each episode. Responses to treatment with antiviral medications were evaluated. Cumulative risk of recurrence was determined using Kaplan-Meier analysis; potential risk factors for recurrence (age, systemic disease, lesion characteristics, corticosteroids) were evaluated using univariate Cox proportional hazard models. RESULTS We identified 20 patients (14 women; median age, 65 years) who met inclusion criteria. Dendriform lesions were pleomorphic with thickened, opaque epithelium. Seven patients had systemic diseases characterized by altered immune function. VZV DNA was identified in 15 of 16 cases tested, and all lesions responded to antiviral therapy. The 1-year incidence of first recurrence was 95.8 lesions per 100 person-years of follow-up. Patients had multiple recurrences, but risk of recurrence appeared to decrease over time. No statistically significant risk factors for recurrence were identified. CONCLUSIONS Late dendriform lesions associated with HZO are foci of productive VZV infection. Lesions can be treated effectively with topical or systemic antiviral agents. Patients can have multiple recurrences of dendriform lesions despite treatment.

Management of prominent iris vascular tufts causing recurrent spontaneous hyphema.

Purpose: To report the management of recurrent, spontaneous hyphema associated with florid iris vascular tufts in a patient presenting for cataract surgery. Methods: Interventional case report and review of the literature; presentation of clinical findings, iris angiography, and the argon laser regimen used to minimize potential corneal complications with increased total treatment energy. Results: An 80-year-old man with a 20-year history of bilateral, recurrent, spontaneous hyphema associated with extensive iris vascular tufts presented with visually significant cataracts. Serial argon laser photocoagulation treatment of the prominent, circumferential iris vascular tufts of the left eye arrested further episodes of spontaneous hyphema and facilitated uneventful cataract surgery. Argon laser parameters were titrated to therapeutic effect during the initial treatment sessions, and sectoral photocoagulation of the circumferential vascular tufts was performed during a 5-month period to accommodate increased laser power and energy. The total energy required to complete treatment of the extensive lesions was substantially more than that in similar previous reports; however, no adverse corneal complications were associated with the laser therapy. Conclusions: This case appears to represent the first description of chronic, bilateral, recurrent spontaneous hyphema associated with iris vascular tufts. Argon laser treatment of symptomatic iris vascular tufts promotes resolution of recurrent, spontaneous hyphema and may serve to mitigate the risk of hemorrhage from these lesions during subsequent intraocular surgery. Conservative management of increased total treatment energy may minimize the potential risk of corneal decompensation with argon laser therapy.

Membrane array analysis of tear proteins in ocular cicatricial pemphigoid.

Purpose. To explore non-invasive, protein-based, membrane array technology as a means to evaluate the global immune and angiogenic profile of tear proteins in patients with active ocular cicatricial pemphigoid (OCP). Methods. Forty-three proteins consisting of cytokines, angiogenic/growth factors, and immunoinflammatory modulators were measured by membrane array in tear samples of four control patients and four OCP patients during active disease and after treatment. Results. Signals for several distinct and consistent molecular entities were upregulated in all four active OCP tear samples relative to controls. In particular, interleukin-8 and matrix metalloproteinase-9 were elevated during active disease and decreased after systemic immunomodulatory therapy. Conclusions. Protein array analysis may provide a well-tolerated assay to monitor levels of inflammatory markers in the tears of OCP patients in response to therapy.

Diagnosis of conjunctival B-cell lymphoma by Polymerase chain reaction heteroduplex analysis

PURPOSE To report a case initially assessed as giant papillary conjunctivitis and subsequently as B-cell lymphoma by the molecular technique of polymerase chain reaction heteroduplex analysis. DESIGN Observational case report. METHODS Clinical, histologic, immunohistochemical, and polymerase chain reaction heteroduplex analysis findings are presented. RESULTS A 32-year-old man developed unilateral blepharoptosis secondary to an extensive palpebral conjunctival follicular-like process. Excisional biopsy showed a dense small lymphocyte infiltrate consistent with benign lymphoid hyperplasia by histology and immunohistologic marker studies. Polymerase chain reaction heteroduplex analysis revealed low-grade B-cell lymphoma, however. Systemic examination was negative. Focal radiation therapy was performed, and preliminary results show no signs of lymphoma. CONCLUSIONS Polymerase chain reaction heteroduplex analysis established a diagnosis of conjunctival B-cell lymphoma in the absence of supporting histology and immunohistochemistry studies. This technique may provide independent, diagnostic distinction between benign lymphoid hyperplasia and low-grade B-cell lymphoma of the ocular adnexa.

Steel wool keratopathy: a clinical sign of chronic inflammation.

Purpose: To introduce into the clinical nomenclature a sign frequently observed in our patients with persistent corneal inflammation associated with herpetic stromal keratitis. Methods: Case reports and review of the literature. Results: Four representative patients with herpesvirus stromal keratitis are presented. Herpes simplex virus-1 (HSV-1) was confirmed by culture in 1 case and by polymerase chain reaction in a second case. In the remaining 2 cases, the diagnosis was made based on characteristic clinical findings for herpes simplex virus and varicella zoster virus (VZV). On clinical examination, all 4 representative cases of stromal keratitis revealed a well-defined, localized region of intertwined, metallic-like, polychromatic material in the corneal stroma, a sign we have termed steel wool keratopathy. We have only rarely observed this finding in patients with stromal keratitis not caused by a herpesvirus. Conclusion: Steel wool keratopathy seems to represent a focal region of stromal degeneration or deposition associated with chronic inflammation. Although we most often observe this finding in patients with stromal keratitis secondary to HSV or VZV, we cannot exclude the possibility that this sign represents the sequelae of chronic/recurrent inflammation rather than a specific pathologic response to herpetic antigens.